Since it was first noted that human chromosomal fragile sites mapped to chromosome bands that were nonrandomly altered by translocations or deletions in neoplasias, it has been proposed that the recombinogenicity of fragile sites, possibly enhanced by environmental carcinogens, could lead to altered expression of oncogenes or tumor suppressor genes at fragile sites (Yunis and Soreng, 1984, Science 226:1199-1204). The corollary of the proposal is that alterations to expression of genes at fragile sites contribute to clonal expansion of the neoplastic cells. FHIT is thus far the only example of a gene at a constitutive fragile region and shows many hallmarks of a tumor suppressor gene (Ohta et al., 1996, Cell 84:587-597).
The FHIT gene is altered by deletion or translocation in a large fraction of many types of cancers, including lung, cervical, gastric and pancreatic (Ohta et al., 1996, Cell 84:587-597; Sozzi et al., 1996, Cell 85:17-26; Hendricks et al., 1997, Cancer Res. 57:2112-2115; Greenspan et al., 1997, Cancer Res. 57:4692-4698; Baffa et al., 1998, Cancer Res. 58:4708-4714; Simon et al., 1998 Cancer Res. 58:1538-1587; Sorio et al., 1999, Cancer Res. 59:1308-1314). FHIT protein is lost or reduced in the majority of these cancers, in a large fraction of other cancer types (Hadaczek et al., 1998, Cancer Res. 58:2946-295; Ingvarsson et al., 1999, Cancer Res. 59:2682-2689; van Heerden et al., 1999, J. Oral Path. Med. 28:433-437), and preneoplastic lesions in the lung (Sozzi et al., 1998, Cancer Res. 58:5032-5037). Nevertheless, acceptance of FHIT as a tumor suppressor has not been universal (Le Beau et al., 1998, Genes Chromosomes Cancer 21:281-289), with some reports suggesting that fragility of the locus alone could account for the occurrence of clonal or oligoclonal genetic alterations at FHIT in cancers. To define the role of FHIT protein in cancer development, a strain of Fhit-deficient mice was established. Surprisingly, these mice develop symptoms analogous to those seen in humans with Muir-Torre Syndrome (MTS), which is characterized by a predisposition for developing a combination of sebaceous and visceral tumors. The Fhit-deficient mice of the invention afford the opportunity for studying Muir-Torre Syndrome in a nonhuman animal.
Citation or discussion of a reference herein shall not be construed as an admission that such is prior art to the present invention.